In utero dietary exposure to endocrine disruptors and l*

描述（由申请方提供）：在人类和啮齿动物模型中，子宫内激素环境升高可能会增加日后发生乳腺癌的易感性。我们的目标是确定饮食成分，当喂养怀孕的大鼠母鼠，结果减少乳腺肿瘤发生的雌性后代。因此，我们给怀孕的大鼠喂食含有木脂素开环异落叶松树脂醇（SDG），n-3多不饱和脂肪酸（PUFA）和纤维的亚麻籽饮食，所有这些都与降低乳腺癌风险有关，并可能降低血清雌激素。然而，我们发现在怀孕期间喂食10%亚麻籽饮食或15%脱脂亚麻籽饮食的母鼠的雌性后代患DMBA诱导的乳腺肿瘤的风险增加。这是令人惊讶的，因为他们的乳腺含有较少的恶性转化的目标（末端芽，TEB），如其他研究者所报道的。亚麻籽的蛋白质成分积累重金属镉的水平超过了世界卫生组织设定的最高标准。由于镉是一种内分泌干扰物，激活雌激素受体，它也损害了修复DMA损伤的能力，我们假设，在子宫内暴露于亚麻籽中的镉会增加以后患乳腺癌的风险。我们的研究有以下具体目标：（1）确定子宫内镉暴露是否增加了以后的乳腺肿瘤发生;（2）确定木脂素SDG、脂肪酸n-3 PUFA或纤维的存在是否改变子宫内镉暴露对乳腺肿瘤发生的影响;和（3）比较DMA损伤修复的变化，包括肿瘤抑制基因Brcal和p53的表达，以及子宫内暴露于亚麻籽、镉或镉、SDG、n-3 PUFA和纤维的大鼠中雌激素诱导的信号通路。SDG、n-3 PUFA和纤维的膳食水平将与10%亚麻籽膳食中存在的那些相似。我们将使用的模型系统是暴露于致癌物DMBA的Sprague道利大鼠，其导致与人类乳腺癌生物学相似的乳腺肿瘤。在这项研究中获得的结果将提供深入了解的机制，在子宫内暴露于亚麻籽可以改变以后的易感性发展乳腺肿瘤。特别是，我们将确定是否在子宫内暴露于镉目前在亚麻籽中的高水平，是关键的介导因素，以及亚麻籽/镉的影响是否涉及雌激素受体信号传导或氧化损伤修复或两者的变化。

DESCRIPTION (provided by applicant): Elevated in utero hormonal environment may increase later susceptibility to develop breast cancer, both in human and rodent models. Our goal has been to identify dietary components that, when fed to pregnant rat dams, results a reduced mammary tumorigenesis among female offspring. Thus, we fed pregnant rats flaxseed diet that contains lignan secoisolariciresinol (SDG), n-3 polyunsaturated fatty acids (PUFAs) and fiber, all that have been linked to reduced breast cancer risk and that potentially reduce serum estrogens. However, we found that female offspring of dams fed 10% flaxseed diet or 15% defatted flaxseed diet during pregnancy were at an increased risk of developing DMBA-induced mammary tumors. This was surprising since their mammary glands contained less targets (terminal end buds, TEBs) for malignant transformation, as also reported by other investigators. The protein component of flaxseed accumulates heavy metal cadmium to the levels exceeding the maximum guidelines set by the World Health Organization. Since cadmium is an endocrine disrupter and activates the estrogen receptor, and it also impairs the ability to repair DMA damage, we hypothesize that in utero exposure to cadmium in flaxseed increases later breast cancer risk. Our study has the following specific aims: (1) determine whether in utero cadmium exposure increases later mammary tumorigenesis; (2) determine whether the presence of lignan SDG, fatty acid n-3 PUFA or fiber modify the effects of in utero cadmium exposure on mammary tumorigenesis; and (3) compare changes in DMA damage repair, including expression of tumor suppressor genes Brcal and p53, and estrogen-induced signaling pathways in rats exposed to flaxseed, cadmium or a combination of cadmium, SDG, n-3 PUFA and fiber in utero. Dietary levels of SDG, n-3 PUFA and fiber will be similar to those present in 10% flaxseed diet. The model system we will use is Sprague Dawley rat exposed to carcinogen DMBA that results mammary tumors that are biologically similar to human breast cancers. Results obtained in this study will provide insight into the mechanisms by which in utero exposure to flaxseed can alter later susceptibility to develop mammary tumors. In particular, we will determine whether in utero exposure to cadmium present at high levels in flaxseed, is the key mediating factor, and whether flaxseed/cadmium's effects involve changes in estrogen receptor signaling or oxidative damage repair or both.